OCD is a severe, heritable condition with a lifetime prevalence of about two percent in world populations. First-degree family members and OCD probands are at a ten-fold higher risk of developing OCD and related disorders. The mode of inheritance is incompletely understood but is likely complex, involving multiple genetic loci of small to moderate effect. Our laboratory has played a leading role in studies of OCD and of its genetics for over 25 years, and was one of the founding sites of multi-center genome-wide project for studies of OCD, partial results of which have recently been reported in the group's publications noted below. In addition, a series of association studies that has identified and evaluated several genes in OCD and related disorders is continuing. In our Lab's collaborative investigations, we have also worked to clarify the fundamental phenotypical features of OCD and related disorders, sometimes designated 'OCD spectrum disorders', in reports published in 2012-2013. We currently have a multifaceted array of compulsive phenotypical features that cut across traditional diagnostic designations (DSM-IV and DSM-5). In continuing efforts, our group and our collaborators have been using latent class modeling to go beyond factor and cluster analyses in order to parse OCD and related disorders by considering underlying features and comorbid disorders (e.g., affective/bipolar disorders) and life stresses. Examples of some sub-disorders that can contribute to OCD but can be found without classic OCD features include our recent and prior studies of Tourette's disorder and hoarding as well as of comorbid affective disorders, including bipolar disorder. Bipolar disorder is also the subject of direct and molecular genetic studies in continuing collaborative investigations with the Bipolar Genetics Consortium group. Studies are ongoing of the role of serotonin, the SLC6A4 gene and other major serotonin genes plus SLC1A1 in OCD and related disorders such as Tourette disorder (in which 50% of patients meet diagnostic criteria for OCD). A manuscript was published this year about the multiple common and rare SLC6A4 variants found to be associated with Tourette's Disorder including the 5HTTLPR, rs25531, rs25532 and SERT I425V variants (Moya et al., 2013). The relationship of SLC6A4 variants to different SRI treatment responses in humans represents an additional illustration of gene-based influences on serotonergic pharmacologic responses, i.e., a new SERT-based pharmacogenomics, directly relevant to the treatment of human neuropsychiatric disorders such as OCD and depression as well as to other serotonin-related human diseases as we have recently reviewed. Recent evidence from treatment and genetic studies suggest that another neurotransmitter system may contribute to OCD. As with SERT in the serotonin system, the neuronal glutamate transporter is a major regulator of glutamate availability. This glutamate transporter, EAAC3, is encoded by the gene SLC1A1 located within the chromosomal region 9p24. Recent evidence from 9p24 gene linkage analyses and candidate gene studies has suggested probable involvement of SLC1A1 in the development of OCD. Our large case-control study of SLC1A1 included a total of over 950 OCD probands and controls collected by our Lab were published this year. In addition, SLC1A1 expression and data were recently evaluated to gain further insights into SLC1A1 function. We found that gene expression of SLC1A1 is heritable in human cell lines. We identified three SNPs in or near SLC1A1 that correlated with gene expression levels. Additionally, two of these SNPs also predicted expression levels in human post-mortem brain tissue, and one SNP was found to have functional consequences in reporter gene studies. We are currently continuing further lab-based studies of this gene using transgenic techniques in mice and Dr. Moya from our Lab has created conditional Slc1a1 mice, one set of which has this gene deleted and another set which preferentially overexpresses this gene in the forebrain. The rational for creating these two opposite functional Slc1a1 mice was based on the equivocal findings from the human SLC1A1 studies regarding whether this gene might be hypofunctional or hyperfunctional in OCD. These investigations, taken together, indicate that SLC1A1, like SLC6A4, is a susceptibility gene for OCD. The expression and database-mining approach that we used provides a new and useful complementary model approach to strengthen future GWAS and candidate rare functional gene studies in neuropsychiatric and other disorders which represent a large public health burden. In fact, seven neuropsychiatric disorders, including OCD, were listed in the 2001 World Health Organizations report as among the leading causes of years of extended disability among adults. Thus these studies are expected to have a considerable public health impact. In additional studies of the genetics of OCD, we focused on candidate genes for OCD based on animal models of some OCD-related compulsive behaviors. These studies thus bring an even sharper focus on OCD subtypes or sub-populations that may be more closely related to specific single genes. Also of note is that our group continues to share our 25+ year collection of DNA and phenotype data with collaborators in the Obsessive-Compulsive Disorder Collaborative Genetics Study (OCGS) and the Obsessive-Compulsive Foundation (OCF) groups, as well as with other intramural and extramural individual collaborators, thus enhancing the global search for underlying contributions to OCD and related disorders that are of major public health concerns. Many papers that were published in the last year that are listed below resulted from these collaborative studies. The collaborative study to which our Lab contributed DNA and phenotype data based at Massachusetts General Hospital yielded a case-control genome association study involving 7022 individuals published in 2012. One of the top signals obtained was in DLGAP1, coding a post-synaptic density (PSD) protein with high similarity to another PSD gene, DLGAP3 (SAPAP3) which we found to have rare variants enriched in OCD patients versus controls, as reported in a 2011 paper from our group and colleagues. The OCF collaborational GWAS was conceived to compliment the earlier OCGS family-based genome linkage study of 299 OCD-affected sibling pairs together with other family members and now constitutes more than 1100 individuals. The OCGS studies generated 20 publications to date, the most recent last year. This study conducted fine mapping followed by SNP association studies of two regions identified in the initial linkage analysis. Associations were identified in or near a set of associated homeobox genes including MEIS2. Two of these form a heterodemeric complex. All three are involved in neurodevelopment and the heterodemeric complex is specifically known to affect development of the striatum, a brain region previously implicated in OCD via human brain imaging studies. Citations numbers of other papers that have referenced our scientific reports number over 35,000 as of August, 2013. The protocol number for this Annual Report is 96-M-0124 and the NCT number is NCT00001548.